Indole derivatives, method for preparating same and pharmaceutical compositions containing same

ABSTRACT

The present invention provides compounds of formula:  
                 
 
and also provides their preparation and the pharmaceutical compositions comprising them. These compounds are ligands of CB 2  cannabinoid receptors.

The present invention relates to new compounds derived from indole whichare ligands of CB₂ cannabinoid receptors, to the process for preparingthem and to the pharmaceutical compositions comprising them.

Δ⁹-THC is the principal active constituent extracted from Cannabissativa (Tuner, 1985; In Marijuana 1984, Ed. Harvey, D Y, IRL Press,Oxford).

Numerous articles have described not only psychotropic effects of thecannabinoids but also their influence on the immune function [HollisterL. E., J. Psychoact. Drugs 24 (1992), 159-164]. Most of the in vitrostudies have shown immunosuppressant effects for the cannabinoids:inhibition of the proliferative responses of T lymphocytes and Blymphocytes, induced by mitogens [Luo, Y. D. et al., Int. J.Immunopharmacol. (1992) 14, 49-56, Schwartz, H. et al., J. Neuroimmunol.(1994) 55, 107-115], inhibition of the activity of cytotoxic T cells[Klein et al., J. Toxicol. Environ. Health (1991) 32, 465-477],inhibition of the microbicidal activity of macrophages and of thesynthesis of TNFα [Arata, S. et al., Life Sci. (1991) 49, 473-479;Fisher-Stenger et al. J. Pharm. Exp. Ther. (1993) 267, 1558-1565],inhibition of the cytolytic activity and of the production of TNFα onthe part of large granular lymphocytes [Kusher et al. Cell. Immun.(1994) 154, 99-108]. In some studies amplification effects wereobserved: an increase in the bioactivity of interleukin-1 by residentmouse macrophages or differentiated macrophage cell lines, caused byincreased levels of TNFα [Zhu et al., J. Pharm. Exp. Ther. (1994) 270,1334-1339; Shivers, S. C. et al. Life Sci. (1994) 54, 1281-1289].

The effects of the cannabinoids are due to an interaction with specifichigh-affinity receptors, coupled to G proteins, present centrally(Devane et al., Molecular Pharmacology (1988), 34, 605-613) andperipherally (Nye et al., J. Pharmacol. and Exp. Ther. (1985), 234,784-791; Kaminski et al., Molecular Pharmacol. (1992), 42, 736-742;Munro et al., Nature (1993), 365, 61-65).

The central effects of the cannabinoids relate to a first type ofcannabinoid receptors (CB₁) which is present primarily in the brain butalso in the periphery. Moreover, Munro et al. [Nature (1993) 365, 61-65]cloned a second type of cannabinoid receptor, called CB₂, which ispresent in the periphery and more particularly on cells of immuneorigin. The presence of CB₂ cannabinoid receptors on lymphoid cells mayexplain the abovementioned immunomodulation exerted by cannabinoidreceptor agonists.

Certain indole derivatives have been cited in the prior art asexhibiting an affinity for CB₂ receptors. Thus patent U.S. Pat. No.5,532,237 describes compounds of formula:

in which the substituents have various values; and patent application EP833 818 describes compounds of formula:

in which the substituents have various values.

Moreover, patent U.S. Pat. No. 4,581,354 describes indole derivativeswhich are active as analgesics and antiinflammatories, of formula:

in which Z may represent oxygen or an NOH group.

The present invention provides compounds of formula:

in which:

-   Ar represents:    -   a) a phenyl which is mono-, di- or trisubstituted by one or more        groups selected from the following: a halogen atom, a        (C₁-C₄)alkyl, a trifluoromethyl, an amino, a nitro, a hydroxyl,        a (C₁-C₄)alkoxy, a (C₁-C₄)alkylsulfanyl, a (C₁-C₄)alkylsulfonyl;    -   b) a naphthyl which is unsubstituted or substituted once or        twice by a halogen atom, a (C₁-C₄)alkyl group or a        trifluoromethyl;-   A represents a C₂-C₆ alkylene radical;-   Y represents a group selected from SR₄, SOR₄, SO₂R₄, SO₂NR₅R₆, N    (R₇) SO₂R₄, OR₄ and NR₇SO₂NR₅R₆;-   R represents hydrogen, a (C₁-C₄)alkyl or (C₂-C₄)alkenyl group or a    group (C₂-C₄)alk-NR₈R₉;-   R₁, R₃ and R′₃ represent each independently of one another hydrogen,    a halogen atom or a hydroxyl, (C₁-C₄)alkyl, trifluoromethyl or    (C₁-C₄)alkoxy group;-   R₂ represents hydrogen or a (C₁-C₄)alkyl group;-   R₄ represents a (C₁-C₄)alkyl group or a trifluoromethyl;-   R₅ and R₆ represent each independently hydrogen or a (C₁-C₄)alkyl    group;-   R₇ represents hydrogen or a (C₁-C₄)alkyl group;-   R₈ and R₉ represent each independently of one another hydrogen or a    (C₁-C₄)alkyl group, or R₈ and R₉ together with the nitrogen atom to    which they are connected constitute a heterocyclic radical    containing from 4 to 7 ring members and being able to contain    another heteroatom selected from a nitrogen, oxygen or sulfur atom,    unsubstituted or substituted by one or more methyl or methoxy    groups;    and their salts, where appropriate, and their solvates.

By halogen is meant a chlorine, bromine, fluorine or iodine atom.

By (C₁-C₄) alkyl is meant a linear or branched C₁-C₄ aliphatic groupsuch as, for example, a methyl, ethyl, propyl, isopropyl, butyl,isobutyl or tert-butyl group.

By (C₂-C₆) or respectively (C₂-C₄) alkylene (alk) is meant a linear orbranched group.

By (C₂-C₄)alkenyl is meant a linear or branched C₂-C₄ unsaturatedaliphatic group, preferably an allyl group.

When R₈ and R₉, together with the nitrogen atom to which they areconnected, constitute a heterocyclic radical this radical is preferablyselected from the following: azetidinyl, pyrrolidinyl, piperidinyl,perhydroazepinyl, piperazinyl, morpholino and thiomorpholino.

Since the compounds of formula (I) are oximes or oxime ethers they existin two forms: syn and anti; the present invention embraces each of thetwo isomers and the mixture of these two isomers in any proportions.

When the compounds of formula (I) include a sulfur atom or an asymmetriccarbon atom, all of the optical isomers, and a mixture thereof in anyproportions, are provided by the invention.

The salts are generally prepared with pharmaceutically acceptable acids,though salts of other acids useful for purifying or isolating compoundsof formula (I) also form part of the invention.

Preferentially the present invention relates to the compounds of formula(I) in which Ar, A, Y, R₁, R₂, R₃, R′₃, R₄, R₅, R₆ and R₇ are as definedabove and R represents hydrogen or a (C₁-C₄)alkyl group.

The present invention most particularly provides compounds of formula(I) in which:

-   Ar represents:    -   a) a phenyl which is mono-, di- or trisubstituted by one or more        groups selected from the following: a halogen atom, a        (C₁-C₄)alkyl, a trifluoromethyl, an amino, a nitro, a        (C₁-C₄)alkoxy, a (C₁-C₄)alkylsulfanyl, a (C₁-C₄) alkylsulfonyl;    -   b) a naphthyl which is unsubstituted or substituted once or        twice by a halogen atom, a (C₁-C₄)alkyl group or a        trifluoromethyl;-   A represents a group (CH₂) n where n represents 2, 3 or 4;-   Y represents a group selected from SR₄, SOR₄, SO₂R₄, SO₂NR₅R₆,    N(R₇)SO₂R₄ and OR₄;-   R represents hydrogen, a (C₁-C₄)alkyl or (C₂-C₄)alkenyl group or a    group (C₂-C₄)alk-NR₈R₉;-   R₁ is in position 7 of the indole ring system and represents a    halogen atom or a (C₁-C₄)alkyl, trifluoromethyl or (C₁-C₄)alkoxy    group;-   R₂ represents hydrogen or a (C₁-C₄)alkyl group;-   R₃ represents a hydrogen or halogen atom or a (C₁-C₄)alkyl group;-   R′₃ is hydrogen;-   R₄ represents a (C₁-C₄)alkyl group;-   R₅ and R₆ represent each independently hydrogen or a (C₁-C₄) alkyl    group;-   R₇ represents hydrogen or a (C₁-C₄)alkyl group;-   R₈ and R₉ represent a (C₁-C₄)alkyl or, together with the nitrogen    atom to which are connected, constitute a heterocyclic radical    selected from: azetidinyl, pyrrolidinyl, piperidinyl,    perhydroazepinyl, piperazinyl, 4-methylpiperazin-1-yl, morpholino    and thiomorpholino;    and their salts, where appropriate, and their solvates.

Preference is given to the compounds of formula (I) in which:

-   Ar represents a phenyl which is mono- or disubstituted by a halogen    atom or a methyl, trifluoromethyl, methoxy, methylsulfanyl or    methylsulfonyl group;-   A represents a group (CH₂)n where n represents 2, 3 or 4;-   Y represents a group SO₂R₄ or NHSO₂R₄;-   R₁ represents a methyl group or a chlorine or bromine atom in    position 7 of the indole ring system;-   R₂ represents a methyl group;-   R₃ is hydrogen or R₃ is in position 6 of the indole ring system and    represents either a chlorine atom or a methyl group;-   R′₃ is hydrogen;-   R₄ represents a methyl or ethyl group;-   R represents hydrogen, a methyl or ethyl group or a —(CH₂)₃N(CH₃)₂    moiety;    and their salts, where appropriate, and their solvates.

The present invention also provides a process for preparing compounds offormula (I), their salts, where appropriate, and their solvates.

This process is characterized in that an aroylindole derivative offormula:

is treated with a hydroxylamine derivative of formula H₂NOR in which Ris as defined above for (I).

The reaction is performed in a polar solvent such as ethanol or apyridine/ethanol mixture at a temperature between the ambienttemperature and the boiling temperature of the solvent.

Where appropriate the compound of formula (I) thus obtained is convertedinto one of its salts or solvates.

The compound obtained is isolated; generally it is composed of a mixtureof the syn and anti isomers of the oxime or oxime ether according to theinvention.

The separation of the syn and anti isomers may be performed using aprocess known to the skilled worker: for example, preparativechromatography.

According to one process of the present invention it is also possible totreat the compound of formula (F) with hydroxylamine (NH₂OH), accordingto the process described above, and, in a subsequent step, to treat theoxime thus obtained, of formula:

with an alkyl or alkenyl halide of formula RX, in which X represents ahalogen atom, or with an alkyl or alkenyl sulfate of formula (R)₂SO₄.

The reaction is performed in the presence of a base such as sodiumhydroxide, using a protic solvent such as ethanol, or in the presence ofsodium hydride in an oxygen-containing solvent such as tetrahydrofuranat a temperature between the ambient temperature and the boilingtemperature of the solvent.

The compounds of formula (F) can be prepared according to variousprocesses, which are described below.

One process, called process A, comprises the following steps:

-   -   a) an indole of formula:        in which R₁, R₂, R₃ and R′₃ are as defined for a compound of        formula (I) is treated with a methylmagnesium halide and with an        acid halide of formula ArCOHal (III), in which Ar is as defined        for the compound of formula (I) and Hal represents a halogen        atom, preferably chlorine;    -   b) the compound thus obtained, of formula:        is treated with a halide of formula Hal-A-Y (V), in which -A-        and Y are as defined for a compound of formula (I) and Hal        represents a halogen atom, preferably bromine, in the presence        of a base.

In step a) of the above process the acylation is performed in a solventsuch as ether.

Step b) is carried out in the presence of a base such as sodiumcarbonate or potassium carbonate, a hydride such as sodium hydride or analkali metal hydroxide such as potassium hydroxide; and in a solventsuch as toluene, DMSO or DMF, at a temperature between the ambienttemperature and the boiling temperature of the solvent. In particular,when the base used is an alkali metal hydroxide, it is also possible toperform step b) in the presence of tris[2-(2-methoxyethoxy)-ethyl]amine(TDA-1), as described in Tetrahedron Lett., 1987, 28, 2963, or in thepresence of a quaternary ammonium salt, such as tetrabutylammoniumhydrogensulfate.

There exists a variant of process A, called process A₁, in which step b)of process A is modified as follows:

-   -   b1) the compound obtained in step a), of formula:        is treated with a compound of formula Z-A-Cl (VI) in which Z        represents either a hydroxyl group or a halogen atom, preferably        bromine, and -A- is as defined for (I);    -   b2) optionally the compound thus obtained, of formula:        is treated with sodium iodide;    -   b3) the compound thus obtained in step b1), of formula (VII), or        in step b2), of formula:        is treated with an anion Y^(Θ), Y being as defined for a        compound of formula (I), to give the compound of formula (I).

When Z represents a halogen atom step b1) is performed in the presenceof a base; when Z represents a hydroxyl group step b1) is performed inthe presence of triphenylphosphine and diethyl azodicarboxylate in asolvent such as dichloromethane.

In step b2), when it is carried out, a solvent such as acetonitrile,acetone or another ketonic solvent is used.

To perform step b3) an anion is used which is obtained by reacting acompound of formula YH(IX) with NaH in a solvent such as DMF.

Process A₁ is particularly preferred for preparing compounds of formula(I) in which Y represents SR₄ or NHSO₂R₄.

According to another variant of process A, called process A₂, a compoundof formula (I) in which Y represents a group SOR₄ or a group SO₂R₄ canbe prepared from a compound of formula (I) in which Y represents a groupSR₄. According to this process, after step b) of process A or step b2)or b3) of process A₁, the following additional step is performed:

-   -   c1) the compound obtained, of formula:        is treated with an oxidizing agent.

As oxidizing agent it is possible to use hydrogen peroxide or3-chloroperbenzoic acid; depending on the number of equivalents ofoxidizing agent used and on the temperature of the reaction, a sulfoxide(I, Y=SOR₄) or a sulfone (I, Y=SO₂R₄) is obtained.

According to another variant of process A, called process A₃, a compoundof formula (I) in which Y represents a group N(R₇)SO₂R₄, in which R₇ isother than H, can be prepared from a compound of formula (I) in which Yrepresents a group NHSO₂R₄. According to this process, after step b) ofprocess A or step b2) or b3) of process A₁ the following additional stepis performed:

-   -   c2) the compound obtained, of formula:        is treated with an alkylating agent in the presence of a base.

As alkylating agent use is made, for example, of a dialkyl sulfate offormula SO₄(R₇)₂ or an alkyl halide of formula R₇Hal, R₇ in theseformulae being as defined for the compounds of formula (I) and Halrepresenting a halogen atom, preferably iodine, in the presence of abase, such as sodium hydride for example.

According to yet another variant of process A, called process A₄, acompound of formula (I) in which Y represents a group SO₂NR₅R₆ can beprepared from a compound of formula (I) in which Y represents a groupSO₂NHR₅. According to this process, after step b) of process A or stepb2) or b3) of process A₁, the following additional step is performed:

-   -   c3) the compound obtained, of formula:        is treated with an alkylating agent in the presence of a base.

As alkylating agent use is made, for example, of a dialkyl sulfate offormula SO₄(R₆)₂ or an alkyl halide of formula R₆Hal, R₆ in theseformulae being as defined for the compounds of formula (I) and Halrepresenting a halogen atom, preferably iodine, in the presence of abase such as sodium hydride.

When it is desired to prepare a compound according to the invention offormula (I) in which Y represents a group NR₇SO₂R₄ or a groupNR₇SO₂NR₅R₆ it is possible to use a variant of process A called processA₅. According to this process:

-   -   b4) the compound obtained in step b1), of formula:        is converted into a compound of formula:        in which R₇ is as defined for (I);    -   c4) it is treated with a halide of formula HalSO₂R₄ or        respectively HalSO₂NR₅R₆, in which R₄, R₅ and R₆ have the        meanings given above for (I).

Step b4) may be carried out by various processes known to the skilledworker: for example, the Delepine reaction (Synthesis, 1979, pp.161-179), the Gabriel reaction (Angew. Chem. Int. Ed. Engl., 1998, 7,919-930) or the reaction of Hebrard (Bull. Soc. Chim. Fr., 1970, 1938).

Step c4) can be carried out in the presence of a base such astriethylamine.

According to one alternative method of process A described above and ofits variants, the alkylation of the indole nitrogen can be performedfirst of all and then the acylation of the compound thus obtained can beperformed. In accordance with this alternative process, called processB:

-   -   i) an indole of formula:        in which R₁, R₂, R₃ and R′₃ are as defined for the compound of        formula (I) is treated with a halide of formula Hal-A-Y (V), in        which -A- and Y are as defined for a compound of formula (I) and        Hal represents a halogen atom, preferably bromine, in the        presence of a base;

ii) the compound thus obtained, of formula:

is treated with an acid halide of formula ArCOHal (III) in which Ar isas defined for the compound of formula (I) and Hal is a halogen atom,preferably chlorine or bromine.

Step i) of the above process is carried out under the conditionsdescribed for step b) of process A. Step ii) is carried out underFriedel-Crafts conditions in the presence of a Lewis acid such as AlCl₃or ethylaluminum dichloride in an inert solvent such as dichloromethaneor dichloroethane, in accordance with the process described in J. Med.Chem., 1995, 38, 3094.

A variety of variants of step i) of process B exist. These variantscorrespond to what was described for process A.

According to variant B₁ of process B:

-   -   i1) an indole of formula:        in which R₁, R₂, R₃ are as defined for the compound of        formula (I) is treated with a compound of formula Z-A-Cl (VI) in        which -A- is as defined for the compound of formula (I) and Z        represents a hydroxyl group or a halogen atom, preferably        bromine;    -   i2) where appropriate the compound thus obtained, of formula:        is treated with sodium iodide;    -   i3) the compound thus obtained in step i1) or in step i2), of        formula:        is treated with an anion of formula Y⁻, Y being as defined for a        compound of formula (I);    -   ii) the compound thus obtained, of formula:        is treated with an acid halide of formula ArCOHal (III) in which        Ar is as defined for the compound of formula (I) and Hal is a        halogen atom, preferably chlorine.

In particular, when it is desired to prepare a compound of formula (I)in which A is (CH₂)₂, it is possible to use techniques which are knownto the skilled worker in order to introduce the alkyl chain ofappropriate length in one of the steps, either of method A or of methodB.

The indoles of formula (II) are known or are prepared by known methodsas described in J. Am. Chem. Soc., 1974, 96, 5495 and 1974, 96, 5512 orin Tetrahedron Lett., 1989, 30, 2129.

The compounds according to the invention have shown a good in vitroaffinity for (CB₂) cannabinoid receptors and a markedly weaker in vitroaffinity for (CB₁) cannabinoid receptors, whether human receptors orrodent receptors. Affinity binding assays were carried out according tothe experimental conditions described by Devane et al. (MolecularPharmacology, 1988, 34, 605-613), with membranes obtained from celllines in which the CB₁ receptors (Matsuda et al., Nature 1990, 346,561-564) and CB₂ receptors (Munro et al., Nature 1993, 365, 61-65) wereexpressed. For human receptors the in vitro affinity for CB₂cannabinoids, expressed in the form of the Ki (inhibition constant), isof the order of nM and the ratio of the affinity for CB₁ receptors tothat for CB₂ receptors is at least 100.

The agonist or antagonist nature of the compounds according to theinvention was demonstrated by the results obtained in models of theinhibition of adenylate cyclase as described in M. Rinaldi-Carmona etal., J. Pharmacol. Exp. Ther. 1996, 278, 871-878 and 1998, 284, 644-650.

The compounds according to the invention likewise possess an in vivoaffinity for the cannabinoid receptors present in mouse spleen when theyare administered orally. The tests were carried out according to theexperimental conditions described by Rinaldi-Carmona et al., J.Pharmacol. Exp. Ther., 1998, 284, 644-650.

The compounds of the present invention are, in particular, activeprinciples for pharmaceutical compositions whose toxicity is compatiblewith their use as medicinal products.

According to one of its aspects the present invention relates to the useof a compound of formula (I) or of one of its pharmaceuticallyacceptable salts or solvates for preparing medicinal products intendedfor preventing or treating any pathology in which CB₂ cannabinoidreceptors are involved.

Mention may be made, for example, of the following diseases orconditions: immune system disorders, particularly autoimmune diseases:psoriasis, lupus erythematosus, connective tissue diseases, Sjogrer'ssyndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactionalarthritis, indifferentiated spondylarthritis, Behcet's disease,autoimmune hemolytic anemias, multiple sclerosis, amyotrophic lateralsclerosis, amyloses, graft rejection, diseases affecting the plasma cellline; allergic diseases: delayed or immediate hypersensitivity, allergicrhinitis, contact dermatitis, allergic conjunctivitis; infectiousparasitic, viral or bacterial diseases: AIDS or meningitis; amylosis,diseases affecting the lines of the lymphohematopoietic system;inflammatory diseases, particularly diseases of the joints: arthritis,rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis,Crohn's disease, inflammatory bowel disease or irritable bowel syndrome(IBD or IBS), pancreatitis; osteoporosis; pain: chronic inflammatorypain, neuropathic pain, acute peripheral pain; eye conditions: ocularhypertension, glaucoma; pulmonary conditions: diseases of therespiratory tract, asthma, chronic bronchitis, chronic obstructivepulmonary disease (COPD), emphysema; diseases of the central nervoussystem and neurogenerative diseases: Tourette's syndrome, Parkinson'sdisease, Alzheimer's disease, senile dementia, chorea, Huntington'schorea, epilepsy, psychoses, depression, spinal cord lesions; migraine,vertigo, vomiting, nausea, in particular that following chemotherapy;cardiovascular diseases, in particular hypertension, arteriosclerosis,heart attack, cardiac ischemia; renal ischemia; cancers: benign skintumors, papillomas and cancerous tumors, tumors of the prostate,cerebral tumors (glioblastomas, medulloepitheliomas, medulloblastomas,neuroblastomas, neuroblastomas, tumors of embryonic origin,astrocytomas, astroblastomas, ependymomas, oligodendrogliomas, plexustumor, neuroepitheliomas, epiphyseal tumor, ependymoblastomas,neuroectodermic, malignant meningiomas, sarcomatoses, malignantmelanomas, schwannomas); gastrointestinal diseases; obesity; anddiabetes.

The use of the compounds according to the invention for preventingand/or treating the abovementioned diseases and also for preparingmedicinal products intended for treating these diseases forms anintegral part of the invention.

The compounds of formula (I) above, or one of their pharmaceuticallyacceptable salts or solvates, can be used at daily doses of from 0.01 to100 mg per kilo of body weight of the mammal to be treated, preferablyat daily doses of from 0.1 to 50 mg/kg. In humans the dose can varypreferably from 0.01 to 4000 mg per day, more particularly from 0.5 to1000 mg, depending on the age of the subject to be treated or on thetype of treatment, i.e., prophylactic or curative.

Thus according to another of its aspects the present invention providespharmaceutical compositions comprising as active principle a compound offormula (I) or one of its pharmaceutically acceptable salts or solvatesand also one or more pharmaceutically acceptable excipients.

In the pharmaceutical compositions of the present invention for oral,sublingual, inhaled, subcutaneous, intramuscular, intravenous, topical,local, intratracheal, intranasal, transdermal, local or rectaladministration, the active principles may be administered in unitadministration forms, in a mixture with conventional pharmaceuticalvehicles, to animals and to human beings.

The appropriate unit administration forms include oral forms such astablets, soft or hard gel capsules, powders, granules, oral solutions orsuspensions, sublingual, buccal, intratracheal, intraocular, intranasaland inhalation administration forms, aerosols, topical and transdermaladministration forms, implants, subcutaneous, intramuscular andintravenous administration forms and rectal administration forms.

For topical administration the compounds according to the invention canbe used in creams, ointments, gels or lotions.

In each dosage unit the active principle of formula (I) is present inthe amounts appropriate for the daily dosages envisaged. Generally eachdosage unit is suitably adjusted according to the dosage and the type ofadministration contemplated—for example, tablets, gel capsules and thelike, sachets, ampoules, syrups and the like, and drops—such that onedosage unit of this kind contains from 0.1 to 1000 mg of activeprinciple, preferably from 0.5 to 250 mg, which must be administered oneto four times per day.

Although these dosages are examples of average situations there may bespecific cases in which higher or lower dosages are appropriate, andsuch dosages also belong to the invention. In accordance with customarypractice the dosage appropriate for each patient is determined by thedoctor in accordance with the method of administration and the age,weight and response of said patient.

It will also be possible to use the compounds according to the inventionfor preparing compositions for veterinary use.

Furthermore, the compounds according to the invention, as they are or inradiolabeled form, can be used as pharmacological tools in humans oranimals, for the detection and labeling of CB₂ cannabinoid receptors.

The following Preparations and Examples illustrate the invention, thoughwithout limiting it.

In the Preparations and in the Examples the following abbreviations areused:

-   -   ether: diethyl ether    -   iso ether: diisopropyl ether    -   DMF: N,N-dimethylformamide    -   THF: tetrahydrofuran    -   DCM: dichloromethane    -   AcOEt: ethyl acetate    -   TDA-1: tris[2-(2-methoxyethoxy)ethyl]amine    -   hydrochloric ether: saturated solution of hydrochloric acid in        diethyl ether    -   Triton B: N-benzyltrimethylammonium hydroxide    -   m.p.: melting point    -   AT: ambient temperature    -   b.p.: boiling temperature

The proton magnetic resonance (¹H NMR) spectra are recorded at 200 MHzin DMSO-d₆, using the DMSO-d₆ peak as reference. The chemical shifts δare expressed in parts per million (ppm). The signals observed areexpressed thus: s: singlet; bs: broad singlet; d: doublet; dd: doubledoublet; t: triplet; dt: double triplet; bt: broad triplet; q: quartet;bq: broad quartet; qt: quintet; m: unresolved multiplet; mt: multiplet;sp: septet.

Preparation of indoles of formula (II).

Preparation 1.1

2-Methyl-7-chloro-1H-indole.

Under a nitrogen atmosphere 42.1 g of 2-chloronitrobenzene are placed in850 ml of THF. The mixture is cooled to −40° C. and then 1.6 1 ofisopropenylmagnesium bromide at 0.5 M in THF are added dropwise. After 1hour at −40° C. with stirring the mixture is hydrolyzed with 400 ml ofsaturated NH₄Cl solution. The aqueous phase is extracted twice withether. The organic phase is dried and then evaporated and the residue ischromatographed on silica, eluting with toluene. This gives 20.3 g ofthe expected compound.

NMR: δ (ppm): 2.4: s: 3H; 6.2: s: 1H; 6.9: t: 1H; 7.1: d: 1H; 7.4: d:1H; 11.2: bs: 1H.

Preparation 1.2

7-Bromo-2-methyl-1H-indole.

27.0 g of 2-bromonitrobenzene are placed in 400 ml of THF. The mixtureis placed under nitrogen and cooled to −55° C. and then 800 ml ofisopropenylmagnesium bromide at 0.5 M in THF are added dropwise. Themixture is left with stirring for 1 hour and then poured into saturatedNH₄Cl solution. It is extracted with ether, the extract is evaporatedand then the residue is taken up in DCM. It is washed with saturatedNaCl solution. It is dried and evaporated and then the residue ischromatographed on silica, eluting with an AcOEt/cyclohexane (1/9; v/v)mixture. This gives 10.7 g of the expected compound.

NMR: δ (ppm): 2.4: s: 3H; 6.2: s: 1H; 6.9: t: 1H; 7.2: d: 1H; 7.4: d:1H; 11.2: bs: 1H.

Preparation 1.3

6,7-Dichloro-2-methyl-1H-indole.

1600 ml of isopropenylmagnesium bromide at 0.5 M in THF are introducedunder nitrogen and cooled to −20° C., 51.2 g of 2,3-dichloronitrobenzenein 250 ml of anhydrous THF are added and then the mixture is left withstirring at −20° C. for 1 hour. The reaction mixture is poured at −20°C. into 1 liter of saturated NH₄Cl solution and diluted with Et₂O andthen the aqueous phase is washed twice with Et₂O. The organic phases arecombined and concentrated to dryness. The product is extracted with DCMand washed twice with water and then with saturated NaCl solution. It isdried and then evaporated and the residue is chromatographed on ahexane/AcOEt (95/5; v/v) mixture. This gives 24.27 g of the expectedcompound, m.p.=70-71° C.

In this way the indole derivatives described in table 1 below wereprepared: TABLE 1

Preparations R₁ R₂ R₃ m.p. ° C./NMR: δ (ppm) 1.1 Cl Me H NMR 1.2 Br Me HNMR 1.3 Cl Me 6-Cl 70-71° C. 1.4 Cl Me 5-Cl 56° C. 1.5 Cl Me 6-Me 2.35:s: 3H; 3.85: s: 3H; 6.15: s: 1H; 6.85: d: 1H; 7.15: d: 1H; 11.20: s: 1H1.6 F Me H 2.40: s: 3H; 6.20: mt: 1H; 6.70-7.30: m: 3H; 11.30: s: 1H 1.7Cl Et H 1.30: t: 3H; 2.80: q: 2H; 6.25: s: 1H; 6.80-7.60: m: 3H; 11.20:bs: 1H

Process A is used to prepare the intermediates of formula (IV) describedbelow: TABLE 2 (IV)

Preparations R₁ R₂ Ar m.p. ° C./NMR: δ (ppm) 2.1 Cl Me2,3-dichlorophenyl 2.2: s: 3H; 7: t: 1H; 7.1 to 7.5: m: 4H; 7.7: d: 1H;12.3: bs: 1H 2.2 Cl Me 2-F,3-CF₃-phenyl 2.4: s: 3H; 7.2: t: 1H; 7.3: d:1H; 7.4: d: 1H; 7.7: mt: 2H; 7.9: t: 1H; 8: t: 1H; 12.6: s: 1H 2.3 Cl Me2-Br,3-Me-phenyl 2.2: s: 3H; 2.4: s: 3H; 7.0: t: 1H; 7.2: m: 2H; 7.3 to7.6: m: 3H 2.4 Br Me 2,3-dichlorophenyl 2.4: s: 3H; 7.0: t: 1H; 7.5: mt:3H; 7.6: t: 1H; 7.9: dd: 1H; 12.3: s: 1H 2.5 OMe Me 1- 120° C.(4-bromonaphthyl)

Process B or process B₁ is used to prepare the intermediates of formula(XII) described below: TABLE 3 (XII)

Pre- NMR/ parations R₁ R₂ R₃ n Y m.p. ° C. Process 3.1 Cl Me H 2 SEt NMRB 3.2 Cl Me H 3 NHSO₂Me NMR B₁ 3.3 Br Me H 3 NHSO₂Me NMR B₁ 3.4 Cl Et H3 NHSO₂Me 98° C. B₁ 3.5 Cl Me 6-Cl 3 NHSO₂Me NMR B₁ 3.6 Cl Me 6-Me 3NHSO₂Me NMR B₁ 3.7 Cl Me H 3 NHSO₂NMe₂ 81° C. B₁ 3.8 H Me H 3 NHSO₂MeNMR B₁

Preparation 3.1: NMR: δ (ppm): 1.25: t: 3H; 2.4 to 2.8: m: 5H; 3: t: 2H;4.8: t: 2H; 7 to 8.2: m: 6H.

Preparation 3.2: NMR: δ (ppm): 1.8: qt: 2H; 2.4: s: 3H; 2.9: s: 3H; 3.0:t: 2H; 4.4: t: 2H; 6.2: s: 1H; 6.9: t: 1H; 7: mt: 2H; 7.4: dd: 1H.

Preparation 3.3: NMR: δ (ppm): 1.8: mt: 2H; 2.4: s: 3H; 2.8: s: 3H; 3.0:qt: 2H; 4.4: t: 2H; 6.2: s: 1H; 6.8: t: 1H; 7.0: t: 1H; 7.2 and 7.4: dd:2H.

Preparation 3.5: NMR: δ (ppm): 1.85: qt: 2H; 2.40: s: 3H; 2.90: s: 3H;3: q: 2H; 4.5: t: 2H; 6.3: s: 1H; 7 to 7.5: m: 3H.

Preparation 3.6: NMR: δ (ppm): 1.85: qt: 2H; 2.40: s: 6H; 2.90: s: 3H;3: q: 2H; 4.5: t: 2H; 6.3: s: 1H; 7 to 7.5: m: 3H.

Preparation 3.8: NMR: δ (ppm): 1.85: qt: 2H; 2.40: s: 3H; 2.90: s: 3H;3.0: q: 2H; 4.15: t: 2H; 6.20: s: 1H; 7 to 7.60: m: 5H.

Preparation 4.1 (Process B₁)

N-(3-(7-Chloro-3-(2-fluoro-3-trifluoromethylphenyl)-2-methyl-1H-indol-1-yl)propyl)methanesulfonamide.

(F): R₁=Cl, R₂=Me, R₃−R′₃=H, Ar=2-fluoro-3-trifluoromethylphenyl,Y=NHSO₂Me, A=(CH₂)_(n), n=3.

A) 7-Chloro-1-chloropropyl-2-methyl-1H-indole.

Under nitrogen 40 g of 7-chloro-2-methyl-1H-indole are placed in 60 mlof toluene with 2.8 g of KOH. After 30 minutes with stirring at AT, 7.7g of 3-chloro-1-bromopropane are added and then the mixture is heated atreflux for 3 hours. The mixture is extracted with ether. The organicphase is washed with water, with 10% HCl solution, with water and withsaturated NaCl solution. It is dried and evaporated to give 6.19 g ofthe expected compound.

B) N-(3-(7-Chloro-2-methyl-1H-indol-1-yl)propyl)methanesulfonamide.

Under nitrogen a mixture is prepared containing 2.2 g of NaH at 60% inoil and 170 ml of DMF, and this mixture is cooled to 0° C. 4.0 g ofNH₂SO₂CH₃ are added and then the mixture is allowed to return to AT and5.0 g of the compound from the preceding step are added. The mixture isheated at 130° C. for 6 hours. It is extracted with DCM and the organicphase is washed with water and then with saturated NaCl solution. It isdried and evaporated and then the residue is chromatographed on silica,eluting with a cyclohexane/AcOEt (30/70; v/v) mixture. This gives 1.92 gof the expected compound.

C)N-(3-(7-Chloro-3-(2-fluoro-3-trifluoromethylphenyl)-2-methyl-1H-indol-1-yl)propyl)methanesulfonamide.

Under nitrogen 0.80 g of the compound from the preceding step and 0.90 gof 2-fluoro-3-trifluoromethylbenzoyl chloride are mixed in 60 ml of DCM.The temperature is lowered to 0° C. and then 34 ml ofdichloroethylaluminum at 1.8 M in toluene are added. The mixture isallowed to return to AT and is then stirred for 15 hours. It isextracted with DCM. The organic phase is washed with water and withsaturated NaCl solution. It is dried and evaporated. The product isrecrystallized from a DCM/ether mixture. This gives 550 mg of theexpected compound, m.p.=168° C.

NMR: δ (ppm): 2: mt: 2H; 2.4: s: 3H; 3.0: s: 3H; 3.2: mt: 2H; 4.7: mt:2H; 7 to 7.5: m: 3H; 7.7: t: 1H; 8: t: 1H; 8.2: t: 1H.

Preparation 4.2

7-Bromo-2-methyl-1-(3-methylsulfinyl)propyl)-1H-indol-3-yl)-2,3-dichlorophenyl)methanone.

(F): R₁=Br, R₂=Me, R₃=R′₃=H, Ar=2,3-dichlorophenyl, Y=-SOMe,A=(CH₂)_(n), n=3.

A) (7-Bromo-2-methyl-1H-indol-3-yl)(2,3-dichlorophenylmethanone).

10.7 g of 7-bromo-2-methyl-1H-indole are placed in 100 ml of THF andcooled to −10° C. At this temperature 22 ml of methylmagnesium bromideat 3M in ether are added. The mixture is allowed to return to AT andthen cooled to −5° C. and 13.5 g of 2,3-dichlorobenzoyl chloride insolution in 80 ml of THF are added dropwise. The mixture is allowed toreturn to AT and then poured into saturated NH₄Cl solution. It isextracted with ether and then the organic phase is washed with 10% NaOHsolution, water and saturated NaCl solution. It is dried and evaporatedand the residue is chromatographed on silica, eluting with anAcOEt/cyclohexane (10/90; v/v) mixture. The resulting productcrystallizes from ether to give 5 g of the expected compound.

B)(7-Bromo-2-methyl-1-(3-chloropropyl)-1H-indol-3-yl)(2,3-dichlorophenyl)methanone.1 g of crushed potassium hydroxide is admixed with 3 g of the compoundfrom the preceding step, 0.3 g of TDA-1 and 100 ml of toluene and thenthe mixture is heated at reflux for 30 minutes and 5 g of1-bromo-3-chloropropane are added. The mixture is allowed to cool to ATand then poured into 100 ml of 10% HCl solution. The mixture isextracted with toluene and then the organic phase is washed with waterand then with saturated NaCl solution. It is dried and evaporated andthe residue is then chromatographed on silica, eluting with DCM. Thisgives 3.25 g of the expected compound, m.p.=139° C.

C)(7-Bromo-2-methyl-1-(3-(methylsulfanyl)-propyl)-1H-indol-3-yl)(2,3-dichlorophenylmethanone)

At AT 3 g of the compound from the preceding step and 0.62 g of MeSNaare mixed in 40 ml of ethanol. The mixture is heated at reflux for 2 anda half hours and then allowed to cool. The mixture is poured into 10%sodium hydroxide solution. The mixture is extracted with ether and thenthe organic phase is washed with saturated NaCl solution. This gives 2 gof the expected compound, m.p.=119° C.

NMR: δ (ppm): 2: mt: 2H; 2.1: s: 3H; 2.4: s: 3H; 2.6: t: 2H; 4.6: t: 2H;7: t: 1H; 7.4 to 7.6: m: 4H; 7.8: dd: 1H.

D)7-Bromo-2-methyl-1-(3-(methylsulfinyl)-propyl)-1H-indol-3-yl)(2,3-dichlorophenyl)methanone.

2.5 g of the compound from the preceding step are placed in 50 ml ofacetic acid and cooled to 10° C. 0.8 ml of H₂O₂ is added with stirringand then the mixture is allowed to return to AT and stirring iscontinued for 1 and a half hours. The mixture is evaporated and thenextracted with AcOEt. The organic phase is washed with 10% NaOHsolution, water and saturated NaCl solution. It is evaporated and theresulting product is recrystallized from an AcOEt/MeOH (9/1; v/v)mixture. This gives 1.1 g of the expected compound, m.p. 137° C.

NMR: δ (ppm): 2.1: qt: 2H; 2.4 and 2.6: 2s: 6H; 2.8 to 3.2: mt: 2H; 4.8:t: 2H; 7.1: t: 1H; 7.5: m: 4H; 7.9: d: 1H.

Preparation 4.3 (process B)

N-(3-(6,7-Dichloro-3-[2-fluoro-3-(trifluoromethyl)benzyl]-2-methyl-1H-indol-1-yl)propyl)methane-sulfonamide.

(F): R₁=R₃=Cl, R₂=Me, R′₃=H, Ar=2F-3-CF₃-phenyl, Y=-NHSO₂Me,A=(CH₂)_(n), n=3.

A) 6,7-Dichloro-1-(3-chloropropyl)-2-methyl-1H-indole.

Under nitrogen 7.84 g of crushed sodium hydroxide, 190 ml of toluene, 7g of 6,7-dichloro-2-methyl-1H-indole, 85 ml of toluene and 0.7 g oftetrabutylammonium hydrogensulfate are introduced. The mixture is heatedat reflux for 30 minutes and then 14 ml of 1-bromo-3-chloropropane areadded and the reflux is maintained for 2 hours. The reaction mixture ispoured into water and the aqueous phase is washed with toluene. It isextracted with toluene and then washed with water and with saturatedNaCl solution. It is dried and evaporated to give 11.3 g of the expectedcompound.

B) 6,7-Dichloro-1-(3-iodopropyl)-2-methyl-1H-indole.

11.3 g of the compound from the preceding step are introduced into 520ml of acetonitrile and 43 g of NaI and then heated at reflux for 3 days.The reaction mixture is poured into water and diluted with toluene andthen the aqueous phase is washed twice with toluene. The organic phasesare combined and then washed with water and then with saturated NaClsolution. They are dried and concentrated to give 13.93 g of theexpected compound.

C) N-[3-(6,7-Dichloro-2-methyl-1H-indol-1-yl)propyl]methanesulfonamide.

Under nitrogen 6.04 g of NaH at 60% are introduced into 400 ml ofanhydrous DMF. The mixture is cooled to 5° C. and then 14.35 g ofmethanesulfonamide in 200 ml of anhydrous DMF are added. After 10minutes with stirring at 5° C., 13.9 g of the compound obtained in thepreceding step in 200 ml of anhydrous DMF are added and the mixture isallowed to return to AT. After 3 hours with stirring the reactionmixture is poured into water and then diluted with DCM. The aqueousphase is washed 3 times with DCM and then the organic phases arecombined. They are washed with water and with saturated NaCl solution.They are dried and concentrated and the residue is then chromatographedon silica, eluting with a cyclohexane/AcOEt (50/50; v/v) mixture. Thisgives 7.43 g of the expected compound.

NMR: δ (ppm): 1.80: mt: 2H; 2.35: s: 3H; 2.60: s: 6H; 2.90: mt: 2H;4.40: t: 2H; 6.30: s: 1H; 7.10: d: 1H; 7.20: mt: 1H; 7.35: d: 1H.

D)N-(3-(6,7-Dichloro-3-[2-fluoro-3-(trifluoromethyl)benzoyl]-2-methyl-1H-indol-1-yl)propyl)methanesulfonamide.

1 g of the compound from the preceding step and 1.35 g of2-fluoro-3-(trifluoromethyl)benzoyl chloride are introduced into 120 mlof DCM. The mixture is cooled to between −20° C. and −25° C. and, usinga syringe, 3.3 ml of dichloroethylaluminum are added. The mixture isallowed to return to ambient temperature and stirring is continued for 3hours. The reaction mixture is poured into water, the aqueous phase iswashed 3 times with DCM and then the organic phases are combined andfiltered over Celite®. The product is washed with 10% NaOH solution,water, 10% HCl solution and then saturated NaCl solution. This gives0.94 g of the expected compound, which crystallizes from ether,m.p.=181° C.

Employing one of the processes described, the compounds of formula IIassembled in the table below were prepared: TABLE 4 (F)

Prepar- m.p. ° C./ Pro- ations R₁ R₂ R₃ n Y Ar NMR cess 4.1 Cl Me H 3NHSO₂Me 2-F-3-CF₃-phenyl NMR B₁ 4.2 Br Me H 3 SOMe 2,3-dichlorophenylNMR A₂ 4.3 Cl 6-Cl 3 NHSO₂Me 2-F-3-CF₃-phenyl 181° C. B 4.4 Cl Me H 2SO₂Et 2-F-3-CF₃-phenyl 187° C. A₂ 4.5 Cl Me H 3 SOMe 2,3-dichlorophenylNMR A₂ 4.6 Br Me H 3 NHSO₂Me 2,3-dichlorophenyl 147° C. A₁ 4.7 Cl Et H 3NMeSO₂Me 2-F-3-CF₃-phenyl NNR A3 4.8 Cl Me H 3 NHSO₂Me 2-Br-3-Me-phenyl 75° C. B₁ 4.9 H Me H 3 NHSO₂Me 2-F-3-CF₃-phenyl 133° C. B₁ 4.10 Cl Me5-Cl 3 NHSO₂Me 2,3-dichlorophenyl  86° C. B₁ 4.11 Cl Me 6-Me 3 NHSO₂Me2-F-3-CF₃-phenyl 146° C. B₁ 4.12 Cl Me H 3 NHSO₂NMe₂ 2,3-dichlorophenyl110-113° C. B₁ 4.13 Cl Me H 3 NHSO₂NMe₂ 2-F-3-CF₃-phenyl 158-160° C. B₁4.14 F Me H 3 NHSO₂Me 2-F-3-CF₃-phenyl 144-150° C. B₁ 4.15 Br Me H 3NHSO₂Me 2-F-3-Cl-phenyl 191° C. B₁ 4.16 Cl Me 6-Me 3 NHSO₂Me2,4-dichlorophenyl 117-120° C. B₁ 4.17 OMe Me H 3 NHSO₂Me1-(4-bromonaphthyl) 72-77° C. A₅

Preparation 4.5: NMR: δ (ppm): 2.1: mt: 2H; 2.4 to 2.6: 2s: 6H; 2.8: mt:2H; 4.7: mt: 2H; 7.1: t: 1H; 7.2 to 7.6: m: 4H; 7.9: dd: 1H.

Preparation 4.7: NMR: δ (ppm): 1.15: t: 3H; 2.00: mt: 2H; 2.80: s: 3H;2.85 to 3.10: m: 5H; 3.25: t: 2H; 4.55: t: 2H; 6.90 to 8.10: m: 6H.

EXAMPLE 1 Compound 1

(I): R₁=7-Cl, R₂=Me, R₃=R′₃=H, Ar=2-fluoro-3-trifluoromethylphenyl,Y=SO₂Me, A=(CH₂)₃, R=H.

N-(3-(7-Chloro-3-((2-fluoro-3-trifluoromethyl)phenyl)(hydroxyimino)methyl-2-methyl-1H-indol-1-yl)propyl)methanesulfonamide.

Under nitrogen 4.45 g of the compound from preparation 4.1 and 6.3 g ofhydroxylamine are placed in a mixture of 25 ml of pyridine and 26 ml ofethanol and the mixture is heated at reflux overnight.

It is concentrated to dryness and then taken up in an ether/2N aqueousHCl solution mixture and the organic phase is washed with water (twice)and then with saturated NaCl solution.

It is dried over MgSO₄ and evaporated and then chromatographed onsilica, eluting with a DCM/MeOH (100/1 to 97/3; v/v) mixture.

This gives 2.72 g of the expected compound, m.p.=172° C.

EXAMPLE 2 Compound 2

(I): R₁=7-Cl, R₂=Me, R₃=R′₃=H, Ar=2-fluoro-3-trifluoromethylphenyl,Y=SO₂Me, A=(CH₂)₃, R=Me.

N-(3-(7-Chloro-3-((2-fluoro-3-trifluoromethyl)phenyl)(methoxyimino)methyl-2-methyl-1H-indol-1-yl)propyl)methanesulfonamide.

Under nitrogen 1 g of the compound from preparation 4.1 and 1.70 g ofO-methylhydroxylamine are placed in a mixture of 7.5 ml of pyridine and11 ml of ethanol and heated at reflux for 3 days. The mixture isconcentrated to dryness and the residue is then taken up in an ether/10%aqueous hydrochloric acid solution mixture.

The aqueous phase is washed twice with ether and the ethereal phases arecombined and then washed with water and with saturated NaCl solution.

They are dried over MgSO₄ and then chromatographed on silica, elutingwith a cyclohexane/AcOEt (50/50; v/v) mixture. This gives 1.06 g of theexpected compound in the form of a glassy solid, m.p.=62-65° C.

EXAMPLE 3 Compound 28

N-(3-(7-Chloro-3-(((3-dimethylamino)propoxyimino)(fluoro-3-trifluoromethyl)phenyl)methyl)-2-methyl-1H-indol-1-yl)propyl)methanesulfonamidehydrochloride.

A) Acetone O-(3-(dimethylamino)propyl)oxime.

Under nitrogen, 1 litre of ethanol and then 46 g of sodium, cut intopieces, are introduced and cooled to 20° C. 73.1 g of acetooxime and 158g of 3-chlorodimethylaminopropane hydrochloride are added and themixture is heated at reflux for 2 hours. After overnight stirring at ATthe NaCl formed is filtered off and then the mixture is acidified with120 ml of concentrated HCl and concentrated to dryness. The residue istaken up in 100 ml of water and then at 10° C. 160 ml of concentratedsodium hydroxide solution are added. The mixture is extracted twice withether and then dried over MgSO₄. The ether is distilled at atmosphericpressure and then the product is distilled under a pressure of 18 mm ofmercury=2400 pascals. This gives 74.1 g of the expected compound.

B) 3-(aminooxy)propyldimethylamine dihydrochloride.

A mixture containing 74.1 g of the compound from the preceding step in330 mg of water and 140 ml of concentrated HCl is heated at refluxovernight. The acetone formed is distilled off and reflux is continuedfor 1 hour. The mixture is concentrated to dryness, ethanol and tolueneare added and then the mixture is concentrated to dryness again. Theresidue is taken up in 200 ml of isopropanol, and 200 ml of ether andthen 200 ml of acetonitrile are added. After 1 hour with stirring thesolid formed is filtered off and rinsed with acetonitrile containing 20%isopropanol and then with ether; it is dried under vacuum over P₂O₅ togive 75 g of the expected compound, m.p.=158° C.

C)N-(3-(7-Chloro-3-(((3-dimethylamino)propoxyimino)(fluoro-3-trifluoromethyl)phenyl)methyl)-2-methyl-1H-indol-1-yl)propyl)methanesulfonamidehydrochloride.

Under nitrogen 0.79 g of the compound from preparation 4.1 and 3 g of3-(aminooxy)propyldimethylamine dihydrochloride are placed in 40 ml ofethanol and the mixture is left with stirring at reflux for 6 hours. Itis concentrated to dryness and the residue is then taken up in an ethylacetate/2N aqueous HCl solution mixture. The organic phase is washedwith saturated NaCl solution and then dried over MgSO₄ and evaporated.It is chromatographed on silica, eluting with a DMC/MeOH (95/5; v/v)mixture. This gives 280 mg of the expected compound, m.p.=68° C.

Working as described in the above examples, the compounds according tothe invention collated in the table below are prepared.

The compounds are characterized by their melting point or their NMRspectrum; in every case it was verified that the NMR spectrum iscompatible with the structure of the compound. TABLE 5 (I)

Com- m.p. ° C./ pounds R₁ R₂ R₃ n Y R Ar NMR 1 Cl Me H 3 SO₂Me H2-F,3-CF₃- 172° C. phenyl 2 Cl Me H 3 SO₂Me Me 2-F,3-CF₃- 62-65° C.phenyl 3 Cl Me H 3 SOMe H 2,3-dichloro- NMR phenyl 4 Cl Et H 3N(Me)SO₂Me H 2-F,3-CF₃- 130-148° C. phenyl 5 Cl Me 6-Me 3 NHSO₂Me H2-F,3-CF₃- 82-84° C. phenyl 6 Cl Me H 3 NHSO₂Me H 2-Br,3-Me- 68-70° C.phenyl 7 Cl Me H 2 SO₂Et H 2-F,3-CF₃- NMR phenyl 8 Cl Me H 3 NHSO₂Me Et2-F,3-CF₃- NMR phenyl 9 H Me H 3 NHSO₂Me Me 2-F,3-CF₃- NMR phenyl 10 BrMe H 3 NHSO₂Me Me 2-F,3-Cl-  49° C. phenyl 11 Cl Me H 3 NHSO₂NMe₂ H2-F,3-CF₃- 146-152° C. phenyl 12 Cl Me 5-Cl 3 NHSO₂Me H 2,3-dichloro-68-73° C. phenyl 13 Cl Me 6-Me 3 NHSO₂Me H 2,4-dichloro- 185-187° C.phenyl 14 Cl Me 6-Me 3 NHSO₂Me Me 2,4-dichloro- 68-70° C. phenyl 15 ClMe 6-Me 3 NHSO₂Me Et 2,4-dichloro- 62-66° C. phenyl 16 Br Me H 3 SOMe Me2,3-dichloro- NMR phenyl 17 F Me H 3 NHSO₂Me Me 2-F,3-CF₃- NMR phenyl 18OMe Me H 3 NHSO₂Me H 1-(4-bromo- 167-170° C. naphthyl) 19 Cl Me H 3NHSO₂NMe₂ H 2,3-dichloro- NMR phenyl 20 Cl Me H 3 NHSO₂NMe₂ Me2,3-dichloro- 53-57° C. phenyl 21 Cl Me H 3 NHSO₂NMe₂ Et 2,3-dichloro-NMR phenyl 22 Cl Me H 3 NHSO₂NMe₂ allyl 2,3-dichloro- NMR phenyl 23 ClMe 6-Cl 3 NHSO₂NMe Me 2-F,3-CF₃- 148-150° C. phenyl 24 Br Me H 3 NHSO₂MeMe 2,3-dichloro-  65° C. phenyl 25 Br Me H 3 NHSO₂Me allyl 2-F,3-Cl-101° C. phenyl 26 Br Me H 3 SOMe H 2,3-dichloro-  63° C. phenyl 27 Cl MeCl 3 NHSO₂Et Me 4-bromo- 82-86° C. naphthyl 28 Cl Me H 3 NHSO₂Me—(CH₂)₃— 2-F,3-CF₃- 158° C. NMe₂ phenyl

EXAMPLE 3

NMR: δ (ppm): 1.90 to 2.30: m: 5H; 2.56: s: 3H; 2.60 to 2.90: m: 2H;4.61: dd: 2H; 6.80 to 7.70: m: 6H; 11.00 to 11.70: m: 1H.

EXAMPLE 7

NMR: δ (ppm): 1.10 to 1.30: m: 3H; 2.20 to 2.4: m: 3H; 3.00 to 3.30: m:2H; 3.50 to 3.80: m: 2H; 4.80 to 5.00: m: 2H; 6.80 to 8.20: m: 6H; 11.60to 11.90: m: 1H.

EXAMPLE 8

NMR: δ (ppm): 1.3: td: 3H; 2.0: m: 2H; 2.30: s: 3H; 3.0: s: 3H; 3.10:bt: 2H; 4.2: d: 2H; 4.6: bt: 2H; 6.8 to 8.0: m: 7H.

EXAMPLE 9: NMR: δ (ppm): 1.80: bq: 2H; 2.20: s: 3H; 2.90: s: 3H; 3.0:bt: 2H; 3.90: d: 3H; 4.20: bt: 2H; 6.80 to 8.0: m: 8H. EXAMPLE 16

NMR: δ (ppm): 1.90 to 2.10: m: 2H; 2.20: s: 3H; 2.60: s: 3H; 2.60 to3.0: m: 2H; 3.90: s: 3H; 4.5 to 4.7: m: 2H; 6.8 to 7.8: m: 6H.

EXAMPLE 17

NMR: δ (ppm): 1.8: mt: 2H; 2.2: s: 3H; 2.8: s: 3H; 2.95: q: 2H; 3.85:2s: 3H; 4.2: mt: 2H; 6.6 to 8.0: m: 7H.

EXAMPLE 19

NMR: δ (ppm): 1.8: mt: 2H; 2.2: 2s: 3H; 2.6: s: 6H; 3.0: q: 2H; 4.45:mt: 2H; 6.7 to 7.8: m: 7H; 11.2 to 11.8: 2s: 1H.

EXAMPLE 21

NMR: δ (ppm): 1.2: t: 3H; 1.8: mt: 2H; 2.2: s: 3H; 2.6: s: 6H; 2.9: q:2H; 4.1: q: 2H; 4.45: mt: 2H; 6.7 to 7.8: m: 7H.

EXAMPLE 22

NMR: δ (ppm): 1.9: mt: 2H; 2.2: s: 3H; 2.65: s: 6H; 3.0: mt: 2H; 4.3 to4.8: m: 4H; 5.2: mt: 2H; 6: mt: 1H; 6.8 to 7.8: m: 7H.

1. A compound of formula:

in which: Ar represents: a) a phenyl which is mono-, di- ortrisubstituted by one or more groups selected from the following: ahalogen atom, a (C₁-C₄)alkyl, trifluoromethyl, amino, nitro, hydroxyl,(C₁-C₄)alkoxy, (C₁-C₄)alkylsulfanyl, or (C₁-C₄)alkylsulfonyl group; b) anaphthyl which is unsubstituted or substituted once or twice by ahalogen atom, a (C₁-C₄)alkyl group or a trifluoromethyl; A represents aC₂-C₆ alkylene radical; Y represents a group selected from SR₄, SOR₄,SO₂R₄, SO₂NR₅R₆, N(R₇)SO₂R₄, OR₄ and NR₇SO₂NR₅R₆; R represents hydrogen,a (C₁-C₄)alkyl or (C₂-C₄)alkenyl group or a group (C₂-C₄)alk-NR₈R₉; R₁,R₃ and R′₃ represent each independently of one another hydrogen, ahalogen atom or a hydroxyl, (C₁-C₄)alkyl, trifluoromethyl or(C₁-C₄)alkoxy group; R₂ represents hydrogen or a (C₁-C₄)alkyl group; R₄represents a (C₁-C₄)alkyl group or a trifluoromethyl; R₅ and R₆represent each independently hydrogen or a (C₁-C₄)alkyl group; R₇represents hydrogen or a (C₁-C₄)alkyl group; R₈ and R₉ represent eachindependently of one another hydrogen or a (C₁-C₄)alkyl group, or R₈ andR₉ together with the nitrogen atom to which they are connectedconstituted a heterocyclic radical containing from 4 to 7 ring membersand being able to contain another heteroatom selected from a nitrogen,oxygen or sulfur atom, unsubstituted or substituted by one or moremethyl or methoxy groups; and its salts, where appropriate, and/or itssolvates.
 2. A compound according to claim I of formula (I) in which: Arrepresents: a) a phenyl which is mono-, di- or trisubstituted by one ormore groups selected from the following: a halogen atom, a (C₁-C₄)alkyl,trifluoromethyl, amino, nitro, (C₁-C₄)alkoxy, (C₁-C₄)alkylsulfanyl, or(C₁-C₄)alkylsulfonyl group; b) a naphthyl which is unsubstituted orsubstituted once or twice by a halogen atom, a (C₁-C₄)alkyl group or atrifluoromethyl; A represents a group (CH₂)_(n) where n represents 2, 3or 4; Y represents a group selected from SR₄, SOR₄, SO₂R₄, SO₂NR₅R₆,N(R₇)SO₂R₄, OR₄ and OR₄; R represents hydrogen, a (C₁-C₄)alkyl or(C₂-C₄)alkenyl group or a group (C₂-C₄)alk-NR₈R₉; R₁ is in position 7 ofthe indole ring system and represents a halogen atom or a (C₁-C₄) alkyl,trifluoromethyl or (C₁-C₄)alkoxy group; R₂ represents hydrogen or a(C₁-C₄)alkyl group; R₃ represents hydrogen, a halogen atom or a(C₁-C₄)alkyl group; R₃ is hydrogen; R₄ represents a (C₁-C₄)alkyl; R₅ andR₆ represent each independently hydrogen or a (C₁-C₄)alkyl group; R₇represents hydrogen or a (C₁-C₄)alkyl group; R₈ and R₉ represent a(C₁-C₄)alkyl or, together with the nitrogen atom to which they areconnected, constitute a heterocyclic radical selected from: azetidinyl,pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl,4-methylpiperazin-1-yl, morpholino and thiomorpholine; and its salts,where appropriate, and and/or its solvates.
 3. A compound according toclaim 1 of formula (I) in which: Ar represents a phenyl which is mono-or disubstituted by a halogen atom, or a methyl, trifluoromethyl,methoxy, methylsulfanyl or methylsulfonyl group; A represents a group(CH₂)_(n) where n represents 2, 3 or 4; Y represents a group SO₂R₄,NHSO₂R₄; R₁ represents a methyl group or a chlorine or bromine atom inposition 7 of the indole ring system; R₂ represents a methyl group; R₃is hydrogen or R₃ is in position 6 of the indole ring system andrepresents either a chlorine atom or a methyl group; R₃ is hydrogen; R₄represents a methyl or ethyl group; R represents hydrogen, a methyl orethyl group or a —(CH₂)₃N(CH₃)₂ moiety; and its salts, whereappropriate, and/or its solvates.
 4. A process for preparing a compoundof formula (I) according to claim 1, its salts, where appropriate,and/or its solvates, wherein an aroylindole derivative of formula:

in which R₁, R₂, R₃, R′₃, A, Y and Ar are as defined in claim 1 istreated with a hydroxylamine derivative of formula H₂NOR in which R isas defined in claim
 1. 5. A pharmaceutical composition comprising asactive principle a compound according to claim
 1. 6. The pharmaceuticalcomposition according to claim 5, containing from 0.1 to 1000 mg ofactive principle, in a unit dosage form in which the active principle ismixed with at least one pharmaceutical excipient.
 7. (canceled)
 8. Amethod for combating any pathology in which CB₂ cannabinoid receptorsare involved which comprises administering to a patient in need thereofan effective amount of a compound according to claim
 1. 9. A methodaccording to claim 8 for combating autoimmune diseases, allergicdiseases, infectious diseases, neurodegenerative diseases,cardiovascular diseases, cancers, gastrointestinal diseases, obesity anddiabetes.
 10. A pharmaceutical composition comprising as activeprinciple a compound according to claim
 2. 11. A pharmaceuticalcomposition comprising as active principle a compound according to claim3.
 12. A method for combating any pathology in which CB₂ cannabinoidreceptors are involved which comprises administering to a patient inneed thereof an effective amount of a compound according to claim
 2. 13.A method for combating any pathology in which CB₂ cannabinoid receptorsare involved which comprises administering to a patient in need thereofan effective amount of a compound according to claim
 3. 14. A methodaccording to claim 12 for combating autoimmune diseases, allergicdiseases, infectious diseases, neurodegenerative diseases,cardiovascular diseases, cancers, gastrointestinal diseases, obesity anddiabetes.
 15. A method according to claim 13 for combating autoimmunediseases, allergic diseases, infectious diseases, neurodegenerativediseases, cardiovascular diseases, cancers, gastrointestinal diseases,obesity and diabetes.